DD202019A5 - PROCESS FOR THE PREPARATION OF 3,4-DISUBSTITUTED 1,2,5-OXADIAZOLE-2-OXIDES - Google Patents

Abstract

1. Claims for the contracting States : BE, CH, DE, FR, GB, IT, LI, NL, SE 3,4-Disubstituted 1,2,5-oxadiazole-2-oxides of the formula I see diagramm : EP0054873,P10,F11 wherein one of the radicals R**1 and R**2 denotes -CH3 and the other denotes -CONHR**3 N(R**4 )2 , see diagramm : EP0054873,P10,F13 see diagramm : EP0054873,P10,F1 see diagramm : EP0054873,P10,F3 -CONHR**3 OR**6 , -CONHR**7 , -CONR**4 R**8 , see diagramm : EP0054873,P10,F5 see diagramm : EP0054873,P10,F6 wherein R**3 denotes an alkylene radical -Cn H2n -, wherein n = 2, 3 or 4, R**4 and R**8 denote -CH3 or - C2 H5 , R**5 denotes -OCH3 or -Cl, R**6 denotes -H or -CH3 , R**7 denotes alkyl having 1 to 4 atoms, cycloalkyl having 5 to 7 C atoms, allyl, or pyridyl methyl, and X denotes -(CH2 )2 -O-(CH2 )2 -, see diagramm : EP0054873,P10,F8 -CH2 CH2 CH2 CH2 - or -CH2 CH2 CH2 CH2 CH2 - and pharmacologically acceptable acid addition compounds thereof. 1. Claims for the contracting State : AT Process for the preparation of 3,4-disubstituted 1,2,5-oxadiazole-2-oxides of the formula I see diagramm : EP0054873,P11,F2 wherein one of the radicals R**1 and R**2 denotes -CH3 and the other denotes -CONHR**3 N(R**4 )2 , see diagramm : EP0054873,P11,F3 see diagramm : EP0054873,P11,F4 see diagramm : EP0054873,P11,F5 -CONHR**3 OR**6 , -CONHR**7 , -CONR**4 R**8 , see diagramm : EP0054873,P11,F7 see diagramm : EP0054873,P11,F8 wherein R**3 denotes an alkylene radical -Cn H2n -, wherein n = 2, 3 or 4, R**4 and R**8 denote -CH3 or -C2 H5 , R**5 denotes -OCH3 or -Cl, R**6 denotes -H or -CH3 , R**7 denotes alkyl having 1 to 4 C atoms, cycloalkyl having 5 to 7 C atoms, allyl, or pyridyl methyl, and X denotes -(CH2 )2 -O-(CH2 )2 -, see diagramm : EP0054873,P11,F11 -CH2 CH2 CH2 CH2 - or -CH2 CH2 CH2 CH2 CH2 - as well as pharmacologically acceptable acid addition compounds thereof, characterised in that for the preparation of compounds of the formula Ia see diagramm : EP0054873,P11,F11 a 3-methyl-1,2,5-oxadiazole-2-oxide-4-carboxylic acid ester of the formula II see diagramm : EP0054873,P12,F1 wherein R**9 denotes alkyl having 1 to 6 C atoms, is reacted with an amine HZ and the amine employed here is selected in such a way that the radical Z, together with the carbonyl group of the ester II, forms the radical R**1 , and the resulting compound is, if appropriate, converted into an acid addition compound or, if appropriate, for the preparation of the compounds of the formula Ib see diagramm : EP0054873,P12,F4 is heated to temperatures from 150 to 220 degrees C, preferably 180 to 200 degrees C, and the resulting compound is, if appropriate, converted into an acid addition compound.

Description

Process for the preparation of 3,4-disubstituted 1,2,5-oxadiazole-2-oxides

Field of application of the invention

The invention relates to a process for the preparation of 3,4-disubstituted 1,2,5-Os: adiazole-2-oxides having valuable pharmacological properties, in particular with effect on the cardiovascular system.

They are used as medicaments, for example for combating or preventing diseases of the cardiovascular system, such as, for example, various types of hypertension S ₉ angina pectoris, etc. »

Characteristic of the known technical solutions

I ¹ Ur fighting or · prevention of diseases of the cardiovascular system has been applied isosorbide dinitrate.

Object of the invention

The aim of the invention is the provision of new compounds with antianginal and antihypertensive effect »

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

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According to the invention 3,4-disubstituted 1,2,5-aladia2ol-2-side of the formula I.

(I)

and their pharinako logically acceptable Säureadditionsrerbindungen.

In formula I mean:

R ¹ for the case that R ^{2 is} -CH ₃ «

-COHHR ³ OR ⁶ , -COMR ⁷ , -COIF ⁴ R ⁸ , r \

-C03J X, -COBHCH

in the event that R is not -CH, and one of the most

1 1

has meanings given for R, R =

R ³ -an alkylene radical -CJS ₀ -, where η = 2, 3 or 4, τ? ⁴ R ⁸ - CH CH

R ⁵ = -OCHo, -Cl,

6 R ⁼ "° H, - CH-3,

R '= alkyl having 1 to 4 C atoms, cycloalkyl having 5 to 7 C atoms, allyl, pyridylmethyl,

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- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -, - (0H ₂ ) ₂ -3Sr-CH ₂ ) ₂ -, -GH ₂ CH ₂ CH ₂ CH ₂ - or

₂₂₂₂₂ ,

R ² = -CH ₇ and for the Pall, that R ¹ a is --OH, has

2 1 ^

R is one of the ones specified for R, except for -CHo »

Meanings.

1 p

It is evident from the above definitions of the radicals R.sup.1 R that in the case of the compounds of the formula I, one

1 p

and only one which is radicals R ¹ or R is -CE ₅ ,

1 P ^

d. H. The radicals R and R in a compound can not simultaneously denote -CHo, but one of them must stand for -CH. .

7 ß

The 'for R (and the below-mentioned R) are the alkyl radicals and representing R "^ alkylene radicals may be straight or branched, R is preferably ₂₂ -. Or CH ₂ CH ₂ CH ₂ -. Of the compounds of formula I

those are preferred in which R = CH-, furthermore

those "which have an -HH grouping in the radical R".

According to the invention, the compounds of the formula I where R ² = -CHO can be prepared by reacting 3-methyl-1,2,5-osadiazole-2-oxide-4-carboxylic acid esters of the formula II with an amine HZ

⁸ RL ' CH ₃

-5- HZ Il \

(II) (Ia)

In this case, R is an alkyl radical having 1 to 6 C atoms, in particular having 1 to 4 C atoms, preferably methyl or ethyl. The amine HZ will look like this

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chosen that the Best Z together with the carbonyl group of the ester II in the compound Ia el therefore the following meanings:

Esters II in the compound Ia forms the radical R ¹ , Z has

// Έ -Μ * ³ - * O -KHR ³ IHCO - 'MR ⁷ ^^ -SHR ³ OR ⁶ , \\ ^ No , -KB ⁴ H ^8,

W ²

The reaction of the compound II with the amine HZ is expediently carried out in a suitable solvent or dispersant. As such solvents or dispersants, for example, alcohols such as methanol, ethanol, i-propanol; furthermore ethers, such as diethyl ether, diosane, tetrahydrofuran; Ketones such as acetone; Hydrocarbons, such as toluene, xylenes, petroleum ether; halogenated hydrocarbons, such as chloroform, chlorobenzene; polar aprotic solvents, such as. B · acetonitrile, dimethylformamide or aqueous solutions of amine HZ be used »The reaction is usually carried out at temperatures of 15 to 25 ⁰ C. But it can also be carried out at temperatures of 0 ⁰ C to the reflux temperature of the solvent or dispersant ·

The compound of formula II with R-ethyl is described in reports of the German Chemical Society 2 &, 2681 (1895) as the ester of peroxydiisonitrosobutyric acid. Compounds of formula II with other R radicals can be

23573 9 1

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in the case of the choice of suitable starting materials, prepare analogously compounds with R =CH.sub.o which have the formula Ib

Ή IT \ c / \ o (Ib),

are prepared from the compounds Ia by thermal rearrangement · The thermal rearrangement is advantageously carried out without Lösungs- or dispersant by heating the substance to temperatures of 150 to 220 ⁰ C, preferably 180 to 200 ⁰ O, performed. The thermal rearrangement is generally complete after 15 to 120 minutes, in most cases after 30 to 60 minutes.

The compounds I which have a basic side chain form salts with inorganic or organic acids. Such acids are, for example, hydrochloric, hydrobromic, phosphoric, sulfuric, otic, lactic, tartaric, acetic, salicylic, benzoic , Citric, ascorbic, adipic and maphthalene disulfonic acid. The acid addition compounds are obtained in known manner by combining the components in a suitable solvent or dispersing agent.

The compounds of the formula I and their pharmacologically acceptable acid addition compounds have valuable pharmacological properties · Particularly pronounced is their effect on the cardiovascular system. They lower blood pressure at low doses, reduce peripheral resistance, and result in a reduction in pulmonary artery pressure with little impact on heart rate

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Reduction of heart work.

The compounds of formula I and their pharmacologically acceptable acid addition salts can therefore be administered to humans as medicines on their own, in mixtures with one another or in the form of pharmaceutical preparations permitting enteral or parenteral administration and containing as active ingredient an effective dose of at least one compound of the formula I or an acid addition salt thereof, in addition to customary pharmaceutically acceptable carriers and additives.

The remedies can be administered orally, .ζ, B, in the form of pills, tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions or aerosol mixtures »The administration can also rectally, z. In the form of suppositories, or parenterally, ζ. In the form of injection solutions, or percutaneously, e.g. B., in the form of ointments or tinctures done.

For the preparation of the pharmaceutical preparations, pharmaceutically inert inorganic or organic carriers are used. For the production of pills, tablets, dragees and hard gelatine capsules z, B lactose, maize starch or derivatives thereof, talc, stearic acid or salts thereof etc. are used as carriers for soft gelatine capsules and suppositories are z. As fats, waxes, semi-solid and liquid polyols, natural or hydrogenated oils, etc. As excipients for the preparation of solutions und.Sirupen are z. As water, sucrose, invert sugar, glucose, polyols, etc. As carriers for the preparation of injection solutions are, for. As water, alcohols, glycerol, polyols, vegetable oils etc ·

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In addition to the active substances and excipients, the pharmaceutical preparations may also contain additives, such as. As fillers, extenders, disintegrants, binders, lubricants, Hetz, stabilizers, emulsifiers, preservatives, sweetening, coloring, flavoring or flavoring, thickening, diluting, buffering agents, further They may also contain two or more compounds of the formula I or their pharmacologically acceptable acid addition salts and other therapeutically active substances.

Such other therapeutically active substances are, for example: β-receptor blockers, such as, for example, B ₀ propranolol, pindolol, metoprolol; Vasodilators, such as B carbochromes; Tranquilizers, such as barbituric acid derivatives, 1,4-benzodiazepines and meprobamate; Diuretics, such as "B""chlorothiazide, the heart-tonic, such as digitalis, antihypertensive agents, such as hydralazine, dihydralazine, prazosin _s clonidine, sauwolfia alkaloids, agents that control fatty acid levels in the blood such as bezafibrate, fenofibrate, thromboprophylaxis drugs, such as phenprocoumon

The compounds of formula I, their pharmacologically acceptable acid addition salts and pharmaceutical preparations containing the compounds of formula I or their pharmacologically acceptable acid addition salts as active ingredients can be used in humans in the control or prevention of diseases of the cardiovascular system, for example as ant Hypertensive remedies!

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the various types of hypertension, in the fight or · refraction of angina, etc. The dosage can vary within wide limits and in each case to adapt to individual circumstances. In general, when administered orally per human subject, a daily dose of about 0.2 to 150 mg, preferably 1 to 30 mg, is adequate. Also in other forms of administration, the daily dose, due to the good absorption of the active ingredients, is in similar ranges, i. H. in general also at 0.2 to 150 mg / human »The daily dose is usually divided into several, eg, 2 to partial administrations.

The pharmaceutical preparations generally contain from the active ingredients of the formula I or their pharmacologically acceptable acid addition salts 0.1 to 50 mg, preferably 0.5 to 10 mg / dose.

Studies on the antianginal and antihypertensive effects of the compounds of formula I were performed on bastard dogs of both sexes in pentobarbital anesthesia (30 to 40 mg / kg iv ") or in urethane-chloralose-anesthetic (3 ml / kg urethane-chloralose mixture iv = 20 mg / kg chloralose and 250 mg / kg urethane). The animals were ventilated with a Bird Mark 7 respirator. The end-expiratory carbon dioxide content (measured with the ura) was between 4> 5 and 5% by volume. Throughout the experiment the animals were given a continuous infusion of pentobarbital with pentobarbital anesthesia. = 4 mg / kg / 6 ml / h to ensure a constant depth of anesthesia; the animals with urethane-chloral-ilarose received no Dauerinfu-. sion. The infusion was given through the cephalic vein *

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After the preparation of the experimental animal, it took about 1 hour to wait until all haemodynamic parameters had set (steady state). Thereafter, the actual experiment was started ·

Systolic and diastolic blood pressure was measured peripherally in the femoral artery via a Statham pressure transducer. A Millar-Tip catheter inserted into the left ventricle via the carotid artery provided the signal for LVEDP (left ventricular end-diastolic pressure) and heart rate. A second tip catheter inserted through the jugular vein detected the mean blood pressure in the pulmonary artery. The results obtained are given in the following table. «

substance dose LVEDP PAP BDm HP / min mg / kg mm / Hg mmHg mmHg (UVO + 0 ISDH 0.05 - 2.1 - 0.7 - 19 + 10 A 0.05 - 3 - 2 - 30 ± ° B 0.1 - 2.5 - 1 - 25 + 0 C 0.05 - 2 - 1 - 35

In the table mean:

LVEDP = left ventricular end-diastolic pressure PAP = mean pulmonary artery pressure BDm = mean peripheral blood pressure HP = heart rate

ISDN = isosorbide dinitrate (reference substance) A = 1,2,5-oxadiazole-2-oxide ~ 4-methyl-3-carboxylic acid methyl

amide B = 1, 2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid methoxyethylamide

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C = 1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid (pyrid-3-yl-methyl-amide)

embodiment

The following examples serve to further explain the invention.

example 1

1,2,5-Oxadia23ol-2-03: id-3-2ne thy 1-4- (car bonic acid e-3-hydroxyethyl amylamide)

19.2 g of 1,2,5-O: xadiazole-2-oxide-3-methyl-4-carboxylic acid ethyl ester are dissolved in 50 ml of ethanol. At 20 ⁰ C, a solution of 6.1 g of ethanolamine in 40 ml of ethanol is added dropwise. The mixture is stirred for 4 hours at 20 ⁰ C, cooled to 0 ⁰ C. The pesticide is filtered off, washed with a little cold ethanol and recrystallized from isopropanol: colorless crystals of Pp 107 to 108 ⁰ C.

In this process, the following compounds can be prepared in the indicated solvents and at the indicated reaction temperatures:

1,2, S-Oxadiazol ^ -oxid ^ -methyl ^ -carboxylic allylamid (oil) in methanol at 15 ⁰ C.

1,2,5-Oxadiazol-2-oside-3-methyl-4-carboxylic acid methylamide (pp 89 to 91 ⁰ C) in water at 0 ⁰ C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid ethylamide (mp 80 to 82 ⁰ C) in i-propanol at 20 ⁰ C.

1,2, 5-0xadiazol-2-o2: id-3-meth.yl-4-carboxylic acid isopropylamide (Pp 94-95 ⁰ C) in toluene at 50 ⁰ C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid (2-diethylamino-ethylamide) (Pp 216 ⁰ C, 3STDS-SaIz) in diethyl ether at reflux temperature »

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1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid (3-diethylaminopropyl) amide (oil) in diethyl ether at reflux temperature, 1,2,5-oxadiazole-2-oxide-3-methyl 4-carboxylic acid - / - S "- (4-omethoxyphenylpiperazin-1-yl) -propylamicl 7 Ci ¹ P 232 ⁰ C, UDS-SaIa) in toluene at 110 ⁰ O.

1,2,5-0xadiazol-2-oxide ~ 3-methyl-4-car bonsäure- (4-o-methoxiphenylpiperazinid) (m.p. 152-153 ⁰ C) in chlorobenzene at 100 ⁰ C.

1,2,5-oxadiazol-2 »os; id-3-methyl-4-carboxylic acid / J- (4-o-chlorophenyl-piperazin-1-yl) -propyl-amide 7 (mp 205 to 20β ⁰ C, decomp. SaIz) in toluene at 110 ⁰ C,

1,2,5-oxadiazole-2-O2: id-3-methyl-4-carboxylic acid _ii / 3 '- (4-o-metiioxiphenyl-piperazin-1-yl) -2-methyl-propylamide7 (J ¹ P 114 to 115 ^° C.) in toluene at 110 ^° C.,

1,2, 5-oxadiazol ~ 2-oxide-3-iaethyl-4 - carbonsäiirecyclopentylaraid (Pp 104 to 106 ⁰ C) in ethanol at 40 ⁰ C.

1,2,5 ~ oxadiazole-2-oxide-3-methyl-4-carbonsäurecyclohesylamid (Pp.95 to 96.5 C ⁰⁾ in ethanol at 60 ⁰ C, 1,2,5-0xadiazol-2-oxide-3 ~ methyl-4 ~ carboxylic acid. (2 - methoxiethyiamid) (Pp 69-70 ⁰ g) in ethanol at 20 ⁰ C. 1,2-B1S- / T, 2,5-oxadiazol-2 ~ oxide-3-methyl -4-carbonylamino7-ethane (Pp 195-200 ⁰ C dec,) propane-carbonylamino7 in ethanol at 25 ⁰ C 1 j 3-3is- / T _s 2 _S 5-oxadiazol-2-oxide ~ 3-methyl-4 ~ (Pp 183 to 186 ⁰ C) in ethanol at 25 ⁰ C 1,2j 5 ~ Oxadiazol-2-ozid-3 ~ methyl-4 ~ carboxylic acid emporolide (mp 75 to 78 ⁰ C) in acetonitrile at 40 ⁰ C, 1 , 2,5 ~ oxadiazol-2 ~ o: Kid-3-methyl-4-carboxylic acid (Pp 91 to 93 ⁰ C) in petroleum ether at 20 ⁰ 1 G., 2s 5-02adiazol-2 ~ O3: id-3- inethyl-4-carboxylic acid pyrrolidide (Pp 65 to 67 ⁰ G) in ethanol at 15 ⁰ G.

1 j 2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid (4-me.thylpiperazid) hydrochloride (Pp 278 to 280 ⁰ C decomp.) In methylene chloride at 25 ⁰ C ₉

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1,2,5-03: adiazole-2-oxide-3-methyl-4-carboxylic acid dimethylamide (mp 70 to 72 ⁰ C) in dimethylformamide / water at 30 ⁰ C.

1,2,5-oxadiazole-2-oxide-3-methyl-4-carboxylic acid (pyrid-3-ylmethylamide) (mp 127 to 129 ⁰ C) in ethanol at 25 ⁰ C.

Example 2 .

1,2, S-Osadiazol ^ -oxide-methyl-methylcarboxylamide

5 g 1,2,5-03: adiazol-2-oxide-3-methyl-4-carboxylic acid are heated without solvent 30 minutes 190 ⁰ G · laughing cooling of the melt, the product mixture by column chromatography (eluent: methylene chloride, column packing: Silica gel). The faster moving fraction is concentrated and stirred with ligroin. The white Peststoff is filtered off and is analytically pure form after drying in vacuo: PP 57 to 59 ⁰ C.

Analogously to this process, the following compounds can be prepared at the reaction temperatures indicated after the compounds:

1, 2, ₃ 5-0xadiazol-2-oxide-4-methyl-3-carboxylic acid ethylamide (oil) 150 ⁰ C.

1,2,5-0xadiazol-2-osid_4-methyl-3-carboxylic acid (2-methosiethylamid) (oil) at 220 ⁰ C.

1,2,5-oxadiazol-2-oxide-4 ~ methyl-3 ~ carboxylic acid isopropylarnid (Fp.65 to 68 ⁰ G) at 200 ⁰ C.

1.2 _i 5-0xadiazol-2-os: id-4-methyl-3-carboxylic acid (2-diethylainino-ethylamide) (Pp 200-202 ⁰ G iJDS salt) at 190 ⁰ C.

1,2,5-Oxadiazole-2-oxide-4-methyl-3-carboxylic acid (4-o-methoxyphenylpiperazinide) (mp 129 to 131 ⁰ C) at 200 ⁰ C.

1,2,5-oxadiazole-2-oxide-4-methyl-3-carboxylic acid cyclopentylamide (Pp 91 to 94 ^° C.) at 190 ^° C.

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1,2,5-Oxadiazol-2-os: id-4-methyl-3-carboxylic acid morpholide (mp 15 to 46 ⁰ C) at 185 ⁰ O.. ,

1 2 ₉ 5-Oxaäiazol-2-oxiä-4-methyl ~ 3-carboxylic acid pyrrolidide (oil) at 180 ⁰ C.

1,2,5-O-2-diazole-2-oxide-4-methyl-3-carboxylic acid (4-methylpiperazide (pp of the hydrochlorides 250 to 252 ⁰ Zers)

195 ⁰ C.

The abbreviation "Zers" means decomposition The term "UDS salt" in connection with the melting point of some of the aforementioned compounds means that it is the melting point of the addition compound with the haphthalene-1,5-disulfonic acid.

The structures of the synthesized compounds can by. the elemental analysis and confirmed by the IR and MR spectra «

Claims (5)

- 14 - 59-771. 18/6/82 Invention claim . 1. A process for the preparation of 3> 4-disubstituted 1,2,5 ~ Osadiazol-2-oxides of the formula I -COHHR ⁷ , -COHR ⁴ R ⁸ , -COH 2, -COHHCH and for the Pall, that R ^ is not equal to -CH ^, and one of the 1 1 R = -GH ,, R ^{3 has} an alkylene radical -C _n H _2n - * where η = 2, 3 or _n2n 4 means. R, R = -CH-j, -C ₂ HcJ
R ⁵ = -OCH ₃ , -Cl R ⁶ - _a -H, -CH ,,.
7 ^ R '= alkyl having 1 to 4 C atoms, cycloalkyl having 5 to 7 C atoms, allyl, pyridylmethyl, CH ₃ X = ~ (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -, - (CH ₂ ) ₂ -H- (CH ₂ ) ₂ -, -CH or -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - - 15 - 59-771.18 18/6/82 and R ² in the case where R ¹ = -CH, 1 Λ has one of the meanings given for R except -CHo, as well as their pharmacologically acceptable acid addition compounds, characterized in that a 3-methyl-1,2,5-os; adiazol-2-02: id-4-carboxylic acid ester of Formula II R ⁸ O-OC ) (ID, wherein R is alkyl having 1 to 6 carbon atoms, is reacted with an amine HZ and thereby the amine is selected so that the radical Z with the carbonyl group of the ester II forms the radical R and the resulting compound is optionally converted into an acid addition compound or optionally for the preparation of the compounds of formula Ib CH ₃ , R ² \> ^{/ N} \ 0 (Ib) to temperatures of 150 to 220 ⁰ C, preferably 180 to 200 ⁰ C, is heated and the resulting "compound is optionally converted into an acid addition compound" Process according to item 1, characterized in that the reaction of the ester of the formula II with the amine HZ is carried out in an absorbent or dispersant at temperatures of from ⁰ ° C to the reflux temperature of the solvent or dispersant. - 16 ~ 59 771 18/6/82 3. A method according to, points 1 or 2, characterized in that H ^{8 is} alkyl having 1 b methyl or ethyl » in that H is alkyl having 1 to 4 G atoms, preferably